NA LRA Watchdog - December 2023

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by

J. Kaitlin Morrison, PhD
Executive Director Clinical Research, UNC Lineberger Comprehensive Cancer Center
Assistant Professor of Medicine- Hematology, University of North Carolina- Chapel Hill

Editor(s):
Joseph Schwartz, MD, MPH
Moffitt Cancer Center and Research Institute
United States

Crystal Ruff, PhD, MBA
Takeda
United Kingdom

The FDA recently released a draft guidance on Decentralized Clinical Trials for Drugs, Biological Products, and Devices. Decentralized Clinical Trials (DCTs) are clinical trials “where some or all of the trial-related activities occur at locations other than traditional clinical trial sites.” Non-traditional trial locations may include trial participant homes or local healthcare facilities.

The Agency indicates that fully decentralized trials are appropriate for investigational products (IPs) that are “simple to administer and use, have well-characterized safety profiles…and do not require complex medical assessments.” When you think about cell and/or gene therapies this is the opposite of how we would describe most of them, particularly when you consider products such as chimeric antigen receptor (CAR) T cell products. Instead, we would consider these products to be very complex, many being studied within phase 1 clinical trials with a primary objective of understanding the safety profile, and many involving complex procedures that can not be conducted via decentralized methods. This definition begs the question, are decentralized clinical trial models relevant for cell and gene therapy? However, the Agency goes on to relay that DCTs can be sub-categorized into fully decentralized or hybrid decentralized trials. Unlike fully decentralized trials, hybrid decentralized trials involve some clinical trial activities being performed at traditional clinical trial sites, whereas others can be performed using decentralized methodologies. FDA indicates that “hybrid decentralized trials may be more appropriate in cases where the administration of an IP or a complex medical assessment needs to be performed at a clinical trial site and some follow-up assessments could be performed remotely through online patient-reported outcome measures, via telehealth, or in-home visits, or by local health care providers (HCPs), as appropriate.” Thus, cell and gene therapy protocols may benefit from these more flexible clinical trial methodologies.

How do hybrid decentralized clinical trials work?

In this guidance, the Agency highlights how sponsors and investigators have the same responsibilities for DCTs as they do for traditional site-based clinical trials and discusses some of the updates that may be required to traditional sponsor and site operations to account for maintaining these responsibilities during decentralization of operations. For example, sponsors should consider updates to their data management plan (DMP), protocols, safety monitoring plan, case report forms (CRFs), and monitoring plan to describe implementation of the decentralized methodologies and how sufficient oversight will remain. Furthermore, the Agency highlights the need for the sponsor to comply with relevant local laws, regulations, and licensing requirements governing medical practice and IP administration. In turn, investigators must develop methodologies to oversee delegated activities and/or tasks and ensure that they are being conducted according to the investigational plan, applicable regulations, and relevant laws. This may necessitate additional training, coordination, or standard operating procedures. The Agency describes how investigators “may delegate trial-related activities to local HCPs to perform trial-related procedures that require in-person interactions with trial participants (e.g., physical examinations and other medical procedures”. For activities requiring more discrete investigator oversight, videoconferencing or other technologies may be used to more closely monitor procedures performed at non-traditional clinical trial sites. For example, video conferencing may be used to oversee the fitting of wearable sensors at the participant’s local HCPs. The Agency then addresses which of these local individuals (e.g., local HCPs) should be included on FDA Form 1572 and how to document oversight of individuals who perform study-related procedures who are not considered to contribute directly or significantly to the clinical trial data. Local HCPs who are “contracted to provide trial-related services that are part of routine clinical practice (e.g., performing physical examinations, reading radiographs, obtaining vital signs) and where a detailed knowledge of the protocol, IP and investigator’s brochure is not necessary should not be listed on Form FDA 1572 as sub investigators.” Instead, these individuals should be included in a task log highlighting their name, affiliation, role, assigned tasks, dates added to the log, and location where the activities are being performed. Even with this allowed delegation, the Agency reminds investigators that they should only enroll subjects that they have the adequate bandwidth to appropriately oversee via the DCT methodologies.

Operationally, the Agency also highlights unique needs for DCTs such as ensuring appropriate capture of and addressing of adverse events (AEs) in order to ensure the safety and welfare of participants. Furthermore, the Agency discusses different methodologies that may facilitate DCTs such as electronic informed consent, packaging and shipping of investigational products, software for activities such as scheduling trial visits, and digital health technologies (DHTs) that may allow for remote transmission of data directly from trial participants. FDA defines the keys to implementing DCTs successfully as appropriate training, oversight, and up-front risk assessment and management.

DCTs are currently in use for gene therapy studies run by many different sponsors. FDA’s Guidance for Industry: Long-Term Follow-up After Administration of Human Gene Therapy Products delineates expectations for long-term follow-up for delayed adverse events, which advises 15 years of follow-up for specific IPs. Based on these requirements, sponsors have worked to find ways to oversee participants for this long period of time in a way that is more convenient for participants and prevents participants from withdrawing from the study. Different hybrid DCT methodologies have been put in place to facilitate these follow-up periods. For example, during long-term follow-up, many participants are seen by local HCPs for yearly required physical exams. In contrast, during the active treatment and the immediate follow-up period, traditional clinical trial methodologies are used where subjects come to a traditional clinical trial site in order to ensure subject safety as the IPs are not simple to administer and use, do not have well-characterized safety profile, and require complex medical assessments.

Why would you want to consider conducting a decentralized trial?

The simple answer to why a sponsor may want to consider using decentralized methodologies is that many of these methodologies are already in use. For example, participants are often able to go to local clinical laboratory facilities for their labs. The motivations behind this local lab usage are simple: enhanced convenience and reduced burden because participants can more easily access these local facilities. The Agency highlights many of the advantages of using decentralized clinical trial methodologies, but all really focus on one key driver: access (access to the patients and access for the patients). Key examples of the advantages of this approach highlighted by the Agency include:

Expanding access to more diverse patient populations
Improving clinical trial efficiencies
Facilitating research on rare diseases
Facilitating research on diseases affecting populations with limited mobility or access to traditional clinical trial sites
Helping to improve trial participant engagement, recruitment, enrollment, and retention

All of this is accomplished by:

Moving geographically towards the patients
Reducing barriers to participation through enhanced convenience for patients and reduced burden for patients and caregivers
Using local healthcare providers potentially reducing cultural or linguistic barriers to participation in clinical trials

Why are more trials being run as DCTs now?

Per the Agency description, many recent advances have optimized the clinical research operations for DCTs. These improvements include both advances in clinical care using electronic communications (e.g., telehealth) that can allow for fewer in-person visits and in information technology such as DHTs that increase what data can be obtained remotely from clinical trial participants.

Conclusion:

Overall, this guidance highlights that even complex clinical trials (such as the ones that are conducted in cell and gene therapy) can benefit from hybrid clinical trial methodologies and provides recommendations from the Agency on how to conduct trials using decentralized methods.

Related Helpful FDA Guidances:

A Risk-Based Approach to Monitoring of Clinical Investigations: Questions and Answers (April 2023)
Draft Guidance for Industry: Digital Health Technologies for Remote Data Acquisition in Clinical Investigations (December 2021)
Enhancing the Diversity of Clinical Trial Populations- Eligibility Criteria, Enrollment Practices, and Trial Designs (November 2020)
Draft Guidance for Industry: Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations: Questions and Answers (March 2023)
Clinical Decision Support Software (September 2022)
Use of Electronic Informed Consent: Questions and Answers (December 2016)
Electronic Source Data in Clinical Investigations

Updates and regulatory news

Health Canada

What’s new in Biologics, radiopharmaceuticals and genetic therapies can be found at:

https://www.canada.ca/en/health-canada/services/drugs-health-products/biologics-radio-pharmaceuticals-genetic-therapies/what-new-biologics-radiopharmaceuticals-genetic-therapies-health-canada.html

Information for health product manufacturers and distributors in relation to COVID-19:

https://www.canada.ca/en/health-canada/services/drugs-health-products/covid19-industry.html

Health-related consultations:

https://www.canada.ca/en/services/health/consultations.html

ICH joint consultations:

https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/international-council-harmonisation/consultations-notices.html#a2

FDA

Warrior Families: Advancing Regenerative Medicine Through Science – October 5, 2023 (Recording is now available)

https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/warrior-families-advancing-regenerative-medicine-through-science-10052023

Workshop for the Identification and Standardization of Methods for Assessing Gene Therapy Product Activity and Comparability and the Evaluation of T-Cell Therapies – November 16-17, 2023

https://www.standardscoordinatingbody.org/events/workshop-for-the-identification-and-standardization-of-methods-for-assessing-gene-therapy-product-activity-and-comparability-and-the-evaluation-of-t-cell-therapies

What’s new for Biologics including Approval and Determination Letters:
https://www.fda.gov/vaccines-blood-biologics/news-events-biologics/whats-new-biologics

COVID-19 Information and Resources:
https://www.fda.gov/emergency-preparedness-and-response/counterterrorism-and-emerging-threats/coronavirus-disease-2019-covid-19

Guidance Documents:
https://www.fda.gov/regulatory-information/search-fda-guidance-documents

Upcoming Conferences:
https://www.fda.gov/vaccines-blood-biologics/news-events-biologics

Updated Approvals and Listings:

Complete List of Licensed Products and Establishments

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2023 Biological Approvals

Guidance Documents CBER is Planning to Publish During Calendar Year 2023: